PROJECT SUMMARY/ABSTRACT Coinfection with hepatitis C virus (HCV) is common among HIV infected patients. HIV exacerbates HCV- related metabolic complications, and coinfected patients have a higher risk of sarcopenia, visceral adiposity, hepatic steatosis, and bone fracture than those with HCV alone, HIV alone, or uninfected persons. Importantly, each of these metabolic complications is associated with morbidity and mortality in HIV+/HCV+ patients. Despite the high prevalence of these abnormalities among HIV+/HCV+ patients and their adverse impact on survival, the underpinnings for the sarcopenia, fat alterations, and skeletal fragility have not been established. Understanding the associations among muscle mass/strength, fat mass/distribution, and bone strength in HIV+/HCV+ patients, how they differ from those of HCV+ and uninfected persons, and their relations with levels of inflammatory cytokines (interleukin-6 and -18; tumor necrosis factor-?) and insulin-like growth factor-1 (IGF-1) will shed light on the relations between HIV/HCV infections and musculoskeletal health, fat distribution, and the role of inflammation. Further, it is unknown if cure of HCV with direct-acting antiviral (DAA) therapy ameliorates these abnormalities, and if the degree of improvement is similar for HIV+/HCV+ and HCV+ patients. To address these knowledge gaps, we will assemble three cohorts of patients: 1) HCV treatment-nave HIV+/HCV+ coinfected patients initiating DAA therapy, 2) treatment-nave HCV+ monoinfected patients initiating DAA therapy, and 3) uninfected persons. We will prospectively follow both HCV infected cohorts from the start of DAA therapy through 12 months after cure of HCV (18-month period) and the uninfected cohort over 18 months. We hypothesize that HIV and HCV-associated inflammation (mediated by interleukin-6, interleukin-18, and tumor necrosis factor-?) and IGF-1 are key determinants of the abnormalities in body composition and bone fragility in HIV+/HCV+ patients. We further hypothesize that cure of HCV will result in significant decreases in these cytokines and an increase in IGF-1 that will lead to improvements in muscle mass/strength, visceral adiposity, hepatic steatosis, and bone strength, but less so for HIV+/HCV+ patients. Aim 1 will compare muscle mass (by dual-energy X-ray absorptiometry), muscle strength; MRI measures of subcutaneous, visceral, and intra-hepatic fat; and bone microarchitecture/strength by high resolution-peripheral quantitative CT across the cohorts at enrollment and evaluate the cytokines and IGF-1 as determinants of these outcomes. Aim 2 will examine the effect of cure of HCV with DAAs on the cytokine and IGF-1 levels in HIV+/HCV+ and HCV+ patients and their associations with subsequent changes in muscle, fat, and bone compared to changes in uninfected persons over the same time. The completion of these aims will address critical knowledge gaps on the determinants (particularly inflammatory cytokines and IGF-1) of sarcopenia, fat alterations, and skeletal fragility in HIV+/HCV+ patients, yield fundamental information on the reversibility of the abnormalities after cure of HCV, and identify determinants of improvement in muscle, fat, and bone strength.